Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function

We review studies with human and nonhuman species that examine the hypothesis that epigenetic mechanisms, particularly those affecting the expression of genes implicated in stress responses, mediate the association between early childhood adversity and later risk of depression. The resulting studies provide evidence consistent with the idea that social adversity, particularly that involving parent-offspring interactions, alters the epigenetic state and expression of a wide range of genes, the products of which regulate hypothalamic-pituitary-adrenal function. We also address the challenges for future studies, including that of the translation of epigenetic studies towards improvements in treatments.     

Chromatin regulation in drug addiction and depression

Alterations in gene expression are implicated in the pathogenesis of several neuropsychiatrie disorders, including drug addiction and depression, increasing evidence indicates that changes in gene expression in neurons, in the context of animal models of addiction and depression, are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular, and bioinformatic approaches that are being used to understand the complex epigenetic regulation of gene expression in brain by drugs of abuse and by stress. These advances promise to open up new avenues for improved treatments of these disorders.     

The epigenetic dimension of Alzheimer's disease: causal,consequence, or curiosity?

Early-onset, familial Alzheimer''s disease (AD) is rare and may be attributed to disease-causinq mutations. By contrast, late onset, sporadic (non-Mendelian) AD is far more prevalent and reflects the interaction of multiple genetic and environmental risk factors, together with the disruption of epigenetic mechanisms controlling gene expression. Accordingly, abnormal patterns of histone acetylation and methylation, as well as anomalies in global and promoter-specific DNA methylation, have been documented in AD patients, together with a deregulation of noncoding RNA. In transgenic mouse models for AD, epigenetic dysfunction is likewise apparent in cerebral tissue, and it has been directly linked to cognitive and behavioral deficits in functional studies. Importantly, epigenetic deregulation interfaces with core pathophysiological processes underlying AD: excess production of Aβ42, aberrant post-translational modification of tau, deficient neurotoxic protein clearance, axonal-synaptic dysfunction, mitochondrial-dependent apoptosis, and cell cycle re-entry. Reciprocally, DNA methylation, histone marks and the levels of diverse species of microRNA are modulated by Aβ42, oxidative stress and neuroinflammation. In conclusion, epigenetic mechanisms are broadly deregulated in AD mainly upstream, but also downstream, of key pathophysiological processes. While some epigenetic shifts oppose the evolution of AD, most appear to drive its progression. Epigenetic changes are of irrefutable importance for AD, but they await further elucidation from the perspectives of pathogenesis, biomarkers and potential treatment.     

Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms

Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may “program” offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment.     

Serotonin-related pathways and developmental plasticity: relevance for psychiatric disorders

Risk for adult psychiatric disorders is partially determined by early-life alterations occurring during neural circuit formation and maturation. In this perspective, recent data show that the serotonin system regulates key cellular processes involved in the construction of cortical circuits. Translational data for rodents indicate that early-life serotonin dysregulation leads to a wide range of behavioral alterations, ranging from stress-related phenotypes to social deficits. Studies in humans have revealed that serotonin-related genetic variants interact with early-life stress to regulate stress-induced cortisol responsiveness and activate the neural circuits involved in mood and anxiety disorders. Emerging data demonstrate that early-life adversity induces epigenetic modifications in serotonin-related genes. Finally, recent findings reveal that selective serotonin reuptake inhibitors can reinstate juvenile-like forms of neural plasticity, thus allowing the erasure of long-lasting fear memories. These approaches are providing new insights on the biological mechanisms and clinical application of antidepressants.     

Post-traumatic stress disorder diagnosis in children: challenges and promises

Children and adolescents experience high rates of potentially traumatic experiences. Many children subsequently develop mental health problems, including post-traumatic stress disorder (PTSD) symptoms. Accurately diagnosing PTSD in children is challenging. This paper reviews the following important issues: (i) the specificity of the PTSD diagnosis; (ii) children who are symptomatic and impaired but do not have enough symptoms for the diagnosis of PTSD; (iii) developmental considerations for preschool and schooi-age children; and (iv) a variety of assessment challenges that reflect the difficulty and complexity of interviewing children and caregivers about these symptoms. Despite these challenges, PTSD remains the best construct for clinical and research work with trauma survivors. Pediatric PTSD criteria are valuable for identifying children at risk and in need of treatment and can be even more helpful when developmentally modified in ways that are discussed.     

Post-traumatic stress disorder and declarative memory functioning: a review

Declarative memory dysfunction is associated with post-traumatic stress disorder (PTSD). This paper reviews this literature and presents two frameworks to explain the nature of this dysfunction: that memory deficits are a product of neurobiological abnormalities caused by PTSD and/or that pre-existing memory deficits serve as a risk factor for the development of PTSD following trauma exposure. Brain regions implicated in declarative memory deficits include the hippocampus and prefrontal cortex, and imaging and biochemistry studies as they relate to memory dysfunction are described. Prospective and twin studies provide support for a risk factor model.     

Evolution of the nervous system: a critical evaluation of how genetic changes translate into morphological changes

Living creatures evolve, and this evolution allows them to adapt to an ever-changing milieu. Two main adaptive strategies coexist. The first involves genetic mutations taking place at the species level. The second strategy occurs at the individual level, and primarily involves changes in chromatin organization and brain circuits. We shall illustrate how the two modes of adaptation are interdependent, and will show the difference in their respective importance depending on the species. It will be proposed that changes in developmental strategies, genetically selected, can lead to more or less epigenetic freedom, sometimes with dramatic consequences. In particular it will be shown, taking chimpanzees and humans as examples, how minor genetic modifications can translate into nonlinear changes in brain structure and cultural practices, placing the two types of primates at a much greater distance than had been anticipated.     

Japanese pharmaceutical and regulatory environment

Drastic regulatory changes in Japan since 1997 have had a considerable impact on the way new medicines are developed. The regulatory authority itself has been transformed. Clinical trials are now performed according to international guidelines. Clinical data generated in one area are acceptable in the rest of the world in some cases through a bridging process that is viewed as only temporary. The future of drug development lies in multinational clinical trials and simultaneous submission to the major regulatory authorities.     

Neurobiological findings in posttraumatic stress disorder: a review

Since posttraumatic stress disorder (PTSD) was first recognized as a psychiatric disorder, it has generated a great deal of scientific interest. Recent studies on the neurobiology of PTSD provide evidence that PTSD is biologically distinct from other types of traumatic and nontraumatic stress responses. This paper reviews three important directions of neurobiological research in PTSD: noradrenergic axis changes and associated alterations in autonomic responsivity neuroendocrine changes involving the hypothalamic-pituitary-adrenocortical (HPA) axis, and neuroanatomy changes involving the hippocampus. Each section reviews the salient aspects of preclinical research on the biology of stress and their bearing on the understanding of PTSD, and summarizes prominent findings from clinical biological studies of PTSD, Tentative models that integrate current findings from the clinical study of PTSD are reviewed. To conclude, the important methodological and empirical issues that need to be addressed by future studies are indicated.     

Protective and damaging effects of stress mediators: central role of the brain

The mind involves the whole body and two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Stress is a condition of the mind-body interaction, and a factor in the expression of disease that differs among individuals. It is notjust the dramatic stressful events that exact their toll, but rather the many events of daily life that elevate and sustain activities of physiological systems and cause sleep deprivation, overeating, and other health-damaging behaviors, producing the feeling of being "stressed out." Over time, this results in wear and tear on the body which is called "allostatic load," and it reflects not only the impact of life experiences but also of genetic load, individual lifestyle habits reflecting items such as diet, exercise, and substance abuse, and developmental experiences that set life-long patterns of behavior and physiological reactivity. Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation by the process known as allostasis, but in the long run allostatic load causes changes in the body that can lead to disease. The brain is the key organ of stress, allostasis, and allostatic load, because it determines what is threatening and therefore stressful, and also determines the physiological and behavioral responses. Brain regions such as the hippocampus, amygdala, and prefrontal cortex respond to acute and chronic stress by undergoing structural remodeling, which alters behavioral and physiological responses. Translational studies in humans with structural and functional imaging reveal smaller hippocampal volume in stress-related conditions, such as mild cognitive impairment in aging and prolonged major depressive illness, as well as in individuals with low self-esteem. Alterations in amygdala and prefrontal cortex are also reported. Besides pharmaceuticals, approaches to alleviate chronic stress and reduce allostatic load and the incidence of diseases of modern life include lifestyle change, and policies of government and business that would improve the ability of individuals to reduce their own chronic stress burden.     

Assessing the benefit: risk ratio of a drug--randomized and naturalistic evidence

Randomized evidence from clinical trials and naturalistic evidence collected from pharmacoepidemiology and pharmacovigilance activities both contribute to the initial and continuous assessment of the benefits and risks of a drug, ie, the balance between therapeutic efficacy and safety risks. Benefit-risk assessment (BRA) mainly relies on a qualitative assessment of quantitative data. Current attempts to quantify BRA are reviewed and discussed, along with the expectations of regulatory authorities such as the Food and Drug Administration and the European Medicines Agency. No method provides a fully satisfactory solution regarding BRA, because it is difficult to reduce its multidimensional aspect to simple metrics, in a context where other therapeutic alternatives play a role. Consistency and transparency are key in this assessment, which is performed throughout the whole drug life cycle. BRA is mainly based on randomized clinical studies during clinical development, and it is continued and consolidated by naturalistic data once the drug is on the market.     

Lifelong posttraumatic stress disorder: evidence from aging Holocaust survivors

Despite the fact that 50 years have passed since the Nazi regime and the Holocaust the psychic sequelae are far from being overcome. The majority of Holocaust survivors and World War II veterans still list their experiences as the "most significant stressors" of their lives. The literature provides ample evidence that posttraumatic stress disorder among survivors persists into old age. However, there is still a need to define the differences in frequency, clinical presentation, severity, and comorbid conditions among aging Holocaust survivors. Age at the time of trauma, cumulative lifetime stress, and physical illness are reported to have a positive association with more severe posttraumatic symptomatology. The presence of comorbid Axis i psychiatric disorders (Diagnostic and Statistical Manual [DSIVI]), has been the focus of research by our group, demonstrating that their interaction with earlier trauma leads to a course of chronic, debilitating disease. Despite reactivation of traumatic symptoms during aging and continuous mental suffering, the majority of Holocaust survivors show good instrumental coping and preserved functioning.     

Neural plasticity: consequences of stress and actions of antidepressant treatment

Neural plasticity is emerging as a fundamental and critical mechanism of neuronal function, which allows the brain to receive information and make the appropriate adaptive responses to subsequent related stimuli. Elucidation of the molecular and cellular mechanisms underlying neural plasticity is a major goal of neuroscience research, and significant advances have been made in recent years. These mechanisms include regulation of signal transduction and gene expression, and also structural alterations of neuronal spines and processes, and even the birth of new neurons in the adult brain. Altered plasticity could thereby contribute to psychiatric and neurological disorders. This article revievi/s the literature demonstrating altered plasticity in response to stress, and evidence that chronic antidepressant treatment can reverse or block the effects, and even induce neural piasiicity-iike responses. Continued elucidation of the mechanisms underlying neural plasticity will lead to novel drug targets that could prove to be effective and rapidly acting therapeutic interventions.     

Genetics of stress response and stress-related disorders

The major findings regarding the genetics of stress response and stress-related disorders are: (i) variations in genes involved in the sympathetic system or in the hypothalamic-pituitary-adrenocortical axis are associated with altered stress responses; (ii) genes related to the renin-angiotensin-aldosterone system or inflammation/immune response show associations with cardiovascular disorders; (iii) genes involved in monoaminergic neurotransmitter systems are associated with bipolar disorder and unipolar depression. The vast majority of these association studies followed a conventional hypothesis-driven approach, restricting the gene selection to established candidates. This very conservative approach retarded our understanding of the complex interplay between genetic factors, stress response, and stress-related disorders. Chip-based whole-genome technologies will open up access to new unbiased and statistically efficient approaches that will help to identify new candidate genes, which should be thoroughly validated in clinical and preclinical confirmatory studies. This, together with the use of new text--and information-mining tools, will bring us closer to integrating all the findings into sophisticated models delineating the pathways from genes to stress response and stress-related disorders.     

Post-traumatic stress disorder: the neurobiological impact of psychological trauma

The classic fight-or-flight response to perceived threat is a reflexive nervous phenomenon thai has obvious survival advantages in evolutionary terms. However, the systems that organize the constellation of reflexive survival behaviors following exposure to perceived threat can under some circumstances become dysregulated in the process. Chronic dysregulation of these systems can lead to functional impairment in certain individuals who become "psychologically traumatized" and suffer from post-traumatic stress disorder (PTSD), A body of data accumulated over several decades has demonstrated neurobiological abnormalities in PTSD patients. Some of these findings offer insight into the pathophysiology of PTSD as well as the biological vulnerability of certain populations to develop PTSD, Several pathological features found in PTSD patients overlap with features found in patients with traumatic brain injury paralleling the shared signs and symptoms of these clinical syndromes.     

Characteristics, experience, and treatment of schizophrenia in China

Assessment of differences in the characteristics, experience, and treatment of schizophrenia between China and the West highlights the importance of the interaction of biological and sociocultural factors in the onset and course of the disorder. China reports a much higher prevalence of schizophrenia in urban areas than in rural areas and, surprisingly a higher prevalence in women than in men. Despite differences in the diagnostic criteria for schizophrenia, the pattern of positive, negative, and cognitive symptoms is similar to that seen in the West. Almost ail medical treatment for schizophrenia is provided from specialized psychiatric hospitals, most of which are situated in urban centers. Antipsychotic medication (often the generic clozapine) is the mainstay of inpatient treatment. China developed a variety of innovative community-based treatment models in the 1980s, but the social and economic changes of the 1990s have made ii difficult to generalize these models. Overall, approximately 70% of the estimated 4.8 million persons with schizophrenia in China do not receive regular treatment.     

Traumatic stress: effects on the brain

Brain areas implicated in the stress response include the amygdala, hippocampus, and prefrontal cortex. Traumatic stress can be associated with lasting changes in these brain areas. Traumatic stress is associated with increased cortisol and norepinephrine responses to subsequent stressors. Antidepressants have effects on the hippocampus that counteract the effects of stress. Findings from animal studies have been extended to patients with post-traumatic stress disorder (PTSD) showing smaller hippocampal and anterior cingulate volumes, increased amygdala function, and decreased medial prefrontal/anterior cingulate function. In addition, patients with PTSD show increased cortisol and norepinephrine responses to stress. Treatments that are efficacious for PTSD show a promotion of neurogenesis in animal studies, as well as promotion of memory and increased hippocampal volume in PTSD.